Despite years of studying human disease and animal models, the exact mechanisms leading to autoimmunity are poorly defined. Although these diseases are considered multifactorial in origin, genetic factors are undoubtedly the most important contributors. Further understanding of these complex syndromes requires definition of the number and nature of the predisposing genes. Advances in molecular genetic methodologies, such as creation of linkage-maps, novel positional cloning techniques, procedures for localizing genes to chromosomes and other methods, now make this task feasible. Using these techniques, identification of genes associated with autoimmune diseases can be undertaken in a broad manner rather than being restricted to certain suspected genes. Such an approach requires no prior knowledge of the genes, factors or mechanisms involved, and focuses directly on the primary genetic contributions rather than secondary or unrelated phenomena. Our research has focused on the prototypic autoimmune disease, systemic lupus erythematosus (SLE). Given the heterogeneity of this disease and the likely involvement of multiple genes, the task of identifying predisposing genes in humans is presently immense, or even impossible. Therefore, this research will be performed in inbred lupus-prone mice. We will create linkage-maps distinguishing selected autoimmune and non- autoimmune mice primarily using simple chromosomal sequence length polymorphic (SSLP) markers. Backcrosses and F2 intercrosses between these mice will be generated, and humoral and histopathologic autoimmune traits with high penetrance will be assessed for their presence, severity, onset and correlations. Mice will then be typed with appropriate SSLP markers and linkage analyses performed to determine the number and chromosomal location of genes associated with each autoimmune trait. Once autoimmune loci are precisely mapped, identification of glomerulonephritis-associated genes will be attempted by searching for known candidate genes in the mouse (and human) genome. Genes not thus identified will be sought by positional cloning techniques. Creation of linkage maps and identification of pleotropic or specific autoimmune trait-associated genes will ultimately provide the means by which the molecular basis of lupus can be defined.